Effect of Type 2 Diabetes Mellitus on the Hypoxia-Inducible Factor 1-Alpha Expression. Is There a Relationship with the Clock Genes?

Identifier:  imarina:7810770

Handle: https://hdl.handle.net/20.500.11797/imarina7810770

Authors:  Lopez-Cano, Carolina; Gutierrez-Carrasquilla, Liliana; Barbe, Ferran; Sanchez, Enric; Hernandez, Marta; Marti, Raquel; Ceperuelo-Mallafre, Vicky; Dalmases, Mireia; Fernandez-Veledo, Sonia; Vendrell, Joan; Hernandez, Cristina; Simo, Rafael; Lecube, Albert

Abstract:
Limited reports exist on the relationships between regulation of oxygen homeostasis and circadian clock genes in type 2 diabetes. We examined whether the expression of Hypoxia-Inducible Factor-1 alpha (HIF-1 alpha) and HIF-2 alpha relates to changes in the expression of clock genes (Period homolog proteins (PER)1, PER2, PER3, Retinoid-related orphan receptor alpha (RORA), Aryl hydrocarbon receptor nuclear translocator-like protein 1 (ARNTL), Circadian locomotor output cycles kaput (CLOCK), and Cryptochrome proteins (CRY) 1 and CRY2) in patients with type 2 diabetes. A total of 129 subjects were evaluated in this cross-sectional study (48% with diabetes). The gene expression was measured by polymerase chain reaction. The lactate and pyruvate levels were used as surrogate of the hypoxia induced anaerobic glycolysis activity. Patients with diabetes showed an increased plasma concentration of both lactate (2102.1 +/- 688.2 vs. 1730.4 +/- 694.4 uM/L,p= 0.013) and pyruvate (61.9 +/- 25.6 vs. 50.3 +/- 23.1 uM/L,p= 0.026) in comparison to controls. However, this finding was accompanied by a blunted HIF-1 alpha expression (1.1 (0.2 to 5.0) vs. 1.7 (0.4 to 9.2) arbitrary units (AU),p <= 0.001). Patients with diabetes also showed a significant reduction of all assessed clock genes' expression. Univariate analysis showed that HIF-1 alpha and almost all clock genes were significantly and negatively correlated with HbA1c concentration. In addition, positive correlations between HIF-1 alpha and the clock genes were observed. The stepwise multivariate regression analysis showed that HbA1c and clock genes independently predicted the expression of HIF-1 alpha. Type 2 diabetes modifies the expression of HIF-1 alpha and clock genes, which correlates with the degree of metabolic control.